European Society of Cardiology: Low-density lipoproteins cause atherosclerotic cardiovascular disease. Pathophysiological, genetic, and therapeutic insights.
It all begins with an idea.
A consensus statement from the European Atherosclerosis Society Consensus Panel
Implications for future prevention of atherosclerotic cardiovascular disease
Extensive evidence on the pathophysiology of ASCVD presented here supplements and extends our earlier review on the causality of LDL based on epidemiological, GWAS, and Mendelian randomization studies, as well as controlled intervention trials with pharmacological agents targeting the LDL receptor. Such evidence, together with the associated molecular mechanisms, has clear implications across the continuum of ASCVD prevention (i.e. primordial, primary, secondary, and tertiary) and is consistent with the central concept derived from genomics that the cumulative arterial burden of LDL-C drives the development and progression of ASCVD and its clinical sequelae.
Furthermore, the pathophysiological evidence supports therapeutic strategies aimed at maintaining very low levels of LDL-C . (e.g. <1 mmol/L or 40 mg/dL) in patients with established ASCVD at very high risk of recurrent events. Such low plasma LDL-C levels are now attainable with the combination of statins and PCSK9 inhibitors (with or without addition of ezetimibe), therapeutic regimens that have proven safety and tolerability. The unequivocal body of evidence for LDL causality in ASCVD will impact on future international recommendations for the management of atherogenic and ASCVD-promoting dyslipidaemias and will guide the rational use of both existing and new therapies. The success of modern programmes of ASCVD prevention will also rely on the practice of precision medicine and patient-centred approaches.
Finally, this thesis has highlighted emerging mechanistic features of atherosclerosis that can potentially lead to evaluation of new therapeutic targets integral to arterial wall biology and plaque stability. Prominent amongst these are endothelial transcytosis of atherogenic lipoproteins, monocyte/macrophage and SMC biology, efferocytosis, inflammation, innate and adaptive immune responses to the intimal retention of apoB-containing lipoproteins and calcification. The future holds great promise but will not be lacking in surprises.
Keywords
Atherosclerosis • Cardiovascular disease • Low-density lipoprotein • Mendelian randomization • Clinical trials • Statin • Ezetimibe • PCSK9 • Causality • Recommendations
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European Society of Cardiology: Low-density lipoproteins cause atherosclerotic cardiovascular disease. Evidence from genetic, epidemiologic, and clinical studies.
It all begins with an idea.
A consensus statement from the European Atherosclerosis Society Consensus Panel
Aims
To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD).
Methods and results
We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL par ticle number and that there are no competing deleterious off-target effects.
Conclusion
Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally estab- lishes that LDL causes ASCVD.
Keywords
Atherosclerosis • Cardiovascular disease • Low-density lipoprotein • Mendelian randomization • Clinical trials • Statin • Ezetimibe • PCSK9 • Causality • Recommendations